To date, the scientific and political focus of sexually transmitted infection (STI) prevention through education, condom use, and vaccine research is clearly inadequate. HIV, Chlamdia, gonorrhea, HSV, and HPV continue to spread, particularly via heterosexual transmission. The tragic reality is that most women are powerless to protect themselves and their unborn children from STI's (1). Development of a safe and effective substance which women can use in the vagina to stem the transmission of all STI's is a critical national and global health priority. Such a chemical barrier--called a microbicide--which can be made available to women to use prior to intercourse can make STI prevention a reality for many (2, 3). We propose to continue a promising and novel microbicide called SAMMA (Sulfuric Acid Modified Mandelic Acid). Thousands of substances have been screened as potential microbicides, and a small number of compounds are undergoing further development in the public and private sector. These first generation microbicides may not be ideal, and have some properties which may limit their safety and or effectiveness. These properties include potential damage to vaginal tissue via cell death or inflammation (4, 5), interference with normal host defenses (6), susceptibility to development of viral resistance (7, 8), and inadequate antimicrobial activity in vivo (9). SAMMA is a very promising second generation microbicide which promises to avoid these potentially significant problems. SAMMA is a simple molecule--colorless, odorless, tasteless, water soluble, stable, and inexpensive. SAMMA has broad antimicrobial activity, is not cytotoxic or inflammatory, has an excellent safety profile, and mechanism of action not susceptible to development of viral resistance. We have preliminary in vitro and animal studies showing that SAMMA) can inhibit fusion and entry of HIV, HSV, gonorrhea, and Chlamydia into vaginal cells. SAMMA also neutralizes sperm (10, 11). We propose to produce a stable, safe SAMMA formulation suitable for human clinical trials and aesthetically acceptable to women and their partners. 1. FORMULATION. We have already established a reliable process for SAMMA synthesis. We will develop several formulations which satisfy requirements for stability, aesthetics, and manufacturability, and are buffered to vaginal acidity. Current research suggests that acid buffering that maintains vaginal pH may significantly improve antimicrobial activity (12). 2. SAFETY. These final formulations will be evaluated in cell culture to assess potentially deleterious effects on normal vaginal flora. Cytotoxicity, i.e., tendency to elicit inflammatory reactions will be tested both in human cell culture and in the mouse vagina. 3. EFFICACY. The new formulations will also be evaluated for activity against sperm, chlamydia and HSV utilizing in vitro assays and the mouse model. [unreadable] [unreadable] [unreadable]